Azetidinone alcohol disulfides and process for cyclization

ABSTRACT

Azetidinone alcohol disulfides are synthesized by reduction of the corresponding aldehydes. The azetidinone alcohol disulfides are the substrates for a process which cyclizes these compounds to 1-oxa β-lactam compounds, employing a cyclizing reagent chosen from the class consisting of divalent mercury salts or trivalent phosphine compounds. The 1-oxa β-lactam compounds produced by this process are intermediates in the synthesis of 1-oxa β-lactam antibiotics.

BACKGROUND OF THE INVENTION

1-oxa β-lactam compounds, which possess the following general structure:##STR1## have recently been the subject of extensive research effortsdue to their antibacterial activity. Specifically, there have been somerecent reports of syntheses of 1-oxa β-lactam compounds substituted withmethyl at the C-3 position. For example, Naylor et al. in "RecentAdvances in the Chemistry of β-Lactam Antibiotics" (J. Elks, ed.), TheChemical Society, London, 1977, p. 204, reported a synthesis of1-oxacephalexin. Similarly, Narisada et al., Heterocycles, 7, 839(1977), were able to prepare several 3-methyl 1-oxa β-lactam compoundswhich exhibited antibacterial activity from four to eight times greaterthan the corresponding cephalosporins. The present application describesand claims novel intermediates which can be employed in the synthesis ofthe aforementioned biologically active 7β-acylamino-7α-alkoxy-3-methyl1-oxa β-lactam compounds. The process for the conversion of suchintermediates into other unclaimed intermediates in the synthesis of theaforementioned 1-oxa β-lactam antibiotics is an alternate aspect of thisinvention.

SUMMARY OF THE INVENTION

This invention is directed to azetidinone alcohol disulfide compounds,encompassing both unsymmetrical azetidinone alcohol disulfide compounds,specifically the aryl 4R[1-(protected carboxy2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-acylamino azetidine]disulfide compounds, and symmetrical azetidinone alcohol disulfidecompounds, specifically the 4R,4'R-bis[1-(protected carboxy2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-acylamino azetidine]disulfide compounds, and the process for cyclizing these compounds tothe corresponding 7α-acylamino-3-methyl 1-oxa β-lactam compounds. Theazetidinone alcohol disulfide compounds of this invention aresynthesized by the sodium cyanoborohydride reduction of thecorresponding aldehydes. The azetidinone alcohol disulfide compounds arethen used as the substrates in the process of this invention, whichinvolves cyclizing the disulfide compounds to the corresponding7α-acylamino-3-methyl 1-oxa β-lactam compounds. The cyclizing reagentsused in the process are chosen from a class consisting of either (a)alkyl, aryl or mixed alkyl-aryl phosphines, or (b) dichloromercury (II),dibromomercury (II), or bis(trifluoroacetato)mercury (II).

The 7α-acylamino-3-methyl 1-oxa β-lactam compounds produced by theprocess of this invention are intermediates in the synthesis of thegeneral class of antibiotically active 7β-acylamino-7α-methoxy-3-methyl1-oxa β-lactam compounds.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds of the following general formulaI, ##STR2## and the process for their conversion to a 1-oxa β-lactamcompound. These compounds are referred to in this application, forconvenience sake, as either "symmetrical azetidinone alcohol disulfide"or "unsymmetrical azetidinone alcohol disulfide" compounds, depending onthe moieties bonded to the disulfide group. In the above terms,"symmetrical" refers to the presence of identically substitutedazetidinone moieties bonded to either end of the disulfide group, while"unsymmetrical" refers to presence of an azetidinone moiety and anaromatic ring moiety bonded to each end disulfide group. The word"alcohol" in the above terms calls attention to the fact that therequisite group is present for cyclization of the disulfide compounds,as opposed to the aldehyde group which must be reduced to the alcoholbefore cyclization can occur.

The 1-oxa β-lactam antibiotics obtained from the azetidinone disulfidesof the invention possess the following bicyclic ring system: ##STR3##wherein R can be hydrogen or a conventional carboxylic acid protectinggroup.

In the formulas contained in this application, the mark " " meansβ-configuration and the dotted line "llll" means α-configuration.

The azetidinone alcohol disulfide compounds of this invention arerepresented by the following general formula I ##STR4## wherein R₁ is anacyl group of the formula ##STR5## wherein R' is (a) C₁ -C₇ alkyl,cyanomethyl, C₁ -C₆ haloalkyl, 4-protected amino-4-protectedcarboxybutyl; or

(b) C₁ -C₆ alkoxy, phenoxy, benzyloxy or 4-methoxybenzyloxy; or

(c) the group --R" wherein R" is phenyl or substituted phenyl whereinthe substituents are 1 or 2 halogens, protected hydroxy, cyano,trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, protected carboxy,protected carboxymethyl, protected hydroxymethyl or protectedaminomethyl; or

(d) an arylalkyl group of the formula R"--(O)_(m) --CH₂ -- wherein R" isas defined above, and m is 0 or 1; or

(e) a substituted arylalkyl group of the formula ##STR6## wherein R'''is R" as defined above, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl; W isprotected hydroxy, protected carboxy, protected amino, or

(f) a heteroarylmethyl group of the formula R''''--CH₂ -- wherein R''''is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl, 5-tetrazolyl, or1-tetrazolyl;

R₂ is a conventional carboxy protecting group and R₃ is another moleculeof the identically substituted azetidinone alcohol moiety bonded to theopposite end of the disulfide group, or is phenyl or a mono-substitutedphenyl group, where the substituents are chloro, methoxy, methyl oracetoxy.

In the following specification, the protecting group designation isomitted for simplicity in nomenclature, but it is understood that, inthe description of the process of this invention, each carboxy, hydroxyor amino group is a protected group.

In the foregoing definitions of the compounds of this invention, theterm "C₁ -C₇ alkyl" refers to methyl, ethyl, n-propyl, n-butyl,isobutyl, pentyl, n-hexyl, cyclohexyl, n-heptyl and like aliphatichydrocarbon groups.

The term "C₁ -C₆ haloalkyl" refers to chloromethyl, bromomethyl,iodomethyl, 2-bromoethyl, 2-chloroethyl, 2-bromopropyl, 2-iodopropyl,2-chlorobutyl, 2-bromo-2-methylpropyl, 2-bromobutyl,2-bromo-2-methylbutyl and like groups.

The term, "protected amino" as employed in the above definition hasreference to an amino group substituted with one of the commonlyemployed amino blocking groups such as the tert-butoxycarbonyl group(t-BOC) the benzyloxycarbonyl group, the 4-methoxybenzyloxycarbonylgroup, the 2,2,2-trichloroethoxycarbonyl group, the trimethylsilylgroup, and like amino protecting groups. The nature of such aminoprotecting groups is not critical so long as the protected aminofunctionality is stable under the reaction conditions describedhereinafter.

The term "protected hydroxy" has reference to any group stable under thereaction conditions of the subsequent step in this synthesis of the1-oxa β-lactam compounds, but readily cleavable thereafter. Such groupsinclude the formyloxy group, the chloroacetoxy group, the benzhydryloxygroup, the trityloxy group, the trimethylsilyl group, and the like.

The term "protected carboxy" has reference to a carboxy group which hasbeen esterified with one of the commonly used carboxylic acid protectingester groups employed to block or protect the carboxylic acidfunctionality while reactions involving other functional sites of thecompound are carried out. Such protected carboxy groups are noted fortheir ease of cleavage by hydrolytic methods to the correspondingcarboxylic acid. Examples of carboxylic acid protecting groups includetert-butyl, p-methoxybenzyl, diphenylmethyl, 2,4,6-trimethylbenzyl,trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityland like ester forming moieties. The nature of such ester forming groupsis not critical so long as the ester formed therewith is stable underthe reaction conditions described hereinafter. Preferred carboxylic acidprotecting groups are diphenylmethyl, 4-methoxybenzyl, and tert-butyl.

In the foregoing definitions, hydroxy, amino, and carboxy protectinggroups are not exhaustively defined. The function of such groups is toprotect the reactive functional groups during the preparation of thedesired products and then be removed without disrupting the remainder ofthe molecule. Many such protecting groups are well known in the art andthe use of other groups equally applicable to the process and compoundsof the present invention, such as those described in J. F. W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, 1973, will berecognized as suitable. Thus, there is no novelty or inventivenessasserted with regard to the "protecting groups" alluded to in thisspecification.

When in the above definition R" represents a substituted phenyl group,R" can be a mono or disubstituted halophenyl group such as4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like;a mono or dihydroxyphenyl group such as 4-hydroxyphenyl,3-hydroxyphenyl, 2,4-dihydroxyphenyl and the like; a cyanophenyl group,for example, 4-cyanophenyl; a mono or disubstituted lower alkylphenylgroup such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-isopropylphenyl, 4-ethylphenyl, 3-n-propylphenyl and the like; a monoor disubstituted lower alkylphenyl ether for example,2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl,4-isopropoxyphenyl, 4-tert-butoxyphenyl, 3-ethoxy-4-methoxyphenyl andthe like. Also, R" represents disubstituted phenyl groups wherein thesubstituents can be different, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl and like disubstituted phenyl groups bearingdifferent substituents.

Illustrative of the acyl groups, ##STR7## where R' is C₁ -C₇ alkyl, orC₁ -C₆ haloalkyl are acetyl, propionyl, butyryl, hexanoyl, chloroacetyl,bromoacetyl and the like.

Representative of the acyl groups ##STR8## when R' is phenyl orsubstituted phenyl are benzoyl, 2,6-dimethoxybenzoyl, 4-chlorobenzoyl,4-methylbenzoyl, 3,4-dichlorobenzoyl, 4-cyanobenzoyl, 3-bromobenzoyl,and 3-aminobenzoyl and like substituted phenylacetyl groups.

Illustrative of the acyl groups ##STR9## when R' is a group of theformula R"--(O)_(m) --CH₂ --, m is 0 and R" is phenyl or substitutedphenyl, are phenylacetyl, 4-chlorophenylacetyl, 3-hydroxyphenylacetyl,3-cyanophenylacetyl, 4-hydroxy-3-methylphenylacetyl,4-bromophenylacetyl, 4-ethoxyphenylacetyl, 3,4-dimethoxyphenylacetyl andthe like; and when m is 1, representative groups are phenoxyacetyl,3-hydroxyphenoxyacetyl, 4-chlorophenoxyacetyl,3,4-dichlorophenoxyacetyl, 2-chlorophenoxyacetyl,4-methoxyphenoxyacetyl, 2-ethoxyphenylacetyl, 3,4-dimethylphenoxyacetyl,4-isopropylphenoxyacetyl, 3-cyanophenoxyacetyl and like substitutedphenoxyacetyl groups.

Illustrative of the acyl groups when R' is a substituted aryl group ofthe formula ##STR10## are the carboxy substituted acyl groups such asthe 2-carboxyl-2-phenylacetyl group of the formula and similar groupswherein the phenyl ring is substituted, for example,2-carboxy-2-(4-chlorophenyl)acetyl, 2-carboxy-2-(4-methoxyphenyl)acetyl,2-carboxy-2-(2-thienyl)acetyl, 2-carboxy-2-(4-methylphenyl)acetyl,2-carboxy-2-(4-(carboxymethyl)phenyl)acetyl,2-carboxy-2-(4-hydroxymethylphenyl)acetyl and like groups.

Representative of the acyl groups when R' is a hydroxy substitutedarylalkyl group are 2-hydroxy-2-(4-methoxyphenyl)acetyl,2-hydroxy-2-(3-chloro-4-hydroxyphenyl)acetyl,2-hydroxy-2-(3-bromophenyl)acetyl,2-hydroxy-2-(3,5-dichloro-4-hydroxyphenyl)acetyl,2-hydroxy-2-(3-chloro-4-methoxyphenyl)acetyl,2-hydroxy-2-(3-chlorophenyl)acetyl,2-hydroxy-2-(4-aminomethylphenyl)acetyl, 2-hydroxy-2-(3-thienyl)acetyl.

When R' is an amino substituted arylalkyl group, acyl groups representedthereby include 2-amino-2-phenylacetyl, 2-amino-2-(4-cyanophenyl)acetyl,2-amino-2-(4-hydroxyphenyl)acetyl, and like groups.

Representative of the acyl group ##STR11## when R' is a heteroarylmethylgroup of the formula R''''--CH₂ -- are 2-thienylacetyl, 3-thienylacetyl,2-furylacetyl, 2-thiazolylacetyl, 1-tetrazolylacetyl, a5-tetrazolylacetyl and the like.

When in the above definition R₃ is a monosubstituted phenyl group wherethe substituents are chloro, methoxy, methyl or acetoxy, the substituentcan be in the ortho, meta or para position. Such substituted R₃ groupsinclude 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl,3-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-acetoxyphenyl,3-acetoxyphenyl and the like.

The compounds of this invention are synthesized by reducing thecorresponding azetidinone aldehyde disulfide with sodiumcyanoborohydride in an acidic medium at ambient temperatures. Ingeneral, the substrate azetidinone aldehyde disulfide is dissolved inwet tetrahydrofuran (THF), the resulting solution's pH is adjusted toabout 3.5, and approximately 1 mole of sodium cyanoborohydride per moleof each aldehyde group present is added to the solution. As thereduction occurs the pH of the reaction solution is maintained betweenabout 3.2 and about 3.6. After an appropriate time (e.g., about 0.5 hourto about 2 hours), the reaction solution is poured into a mixturecomposed of saturated sodium chloride solution and ethyl acetate. Thedesired azetidinone alcohol disulfide can be subsequently isolated fromthe ethyl acetate layer.

The above procedure used to synthesize azetidinone alcohol disulfides byreducing the corresponding azetidinone aldehyde disulfide was adoptedfrom the procedures set forth in R. F. Borch, M. D. Bernstein, and H. D.Durst, Journal of the American Chemical Society, 93 2897 (1971).

The process of this invention for preparing the 7α-acylamino-3-methyl1-oxa β-lactam compounds comprises reacting the azetidinone disulfidealcohol compounds of this invention with a cyclization reagent selectedfrom among the group consisting of divalent mercury compound or atrivalent phosphorus compound in an inert organic solvent to give thedesired 1-oxa β-lactam compound. The process of this invention isillustrated by the following general reaction scheme: ##STR12##

In the above general formula, R₁, R₂ and R₃ are as described before, Xis chloro, bromo or trifluoroacetato and each R₅ is independently C₁ toC₇ alkyl, phenyl or phenyl substituted with C₁ to C₄ alkyl or C₁ to C₄alkoxy.

The process of this invention is carried out by reacting an azetidinonedisulfide alcohol with at least about 1 mole of the cyclization reagentper mole of the disulfide in an inert organic solvent in an inertatmosphere.

The process can be carried out at ambient temperatures, however, withthe divalent mercury reagent cyclization proceeds at somewhat lower orhigher temperatures as well, for example, between about 0° C. and about45° C. When in the process a phosphine, (R₅)₃ P, is used as thecyclizing agent the process proceeds best at somewhat elevatedtemperatures, for example, between about 40° C. to about 65° C. Theprocess employing the phosphine cyclizing reagent can, however, becarried out over a broader temperature range of about 0° C. to about100° C.

Although at least about 1 molar equivalent of either the mercury orphosphorus cyclization reagent is required for complete conversion, itis preferable to employ between about 4 and about 5 moles of the mercurycyclization reagent or between about 1.5 and about 2.5 moles of thephosphorus cyclization reagent per mole of the disulfide substrate.

Inert solvents employed in the process are those which are unreactivewith the cyclizing reagent, the azetidinone disulfide and thecyclization product. Solvents used in the process when a divalentmercury reagent is the cyclizing agent are preferably somewhat polarorganic solvents, (e.g. acetonitrile) owing to the enhanced solubilityof the mercury reagents in these solvents. The process can also proceedwith a divalent mercury reagent in less polar solvents, for example,methylene chloride.

Examples of inert organic solvents that can be employed when thetrivalent phosphine reagent is used include methylene chloride,1,2-dichloroethane, chlorobenzene, 1,1-dibromo-2-chloroethane, benzene,toluene, xylenes, cyclohexane, cyclopentane, 2-methylbutane,2,2,4-trimethylpentane, hexane, heptane, acetonitrile, benzonitrile,pyridine, piperidine, pyrrolidine, and the like. 1,2-Dichloroethane isthe preferred solvent for the process where the trivalent phosphoruscyclization reagent is employed. However, chloroform and carbontetrachloride cannot be used as solvents when the trivalent phosphinereagents is used as the cyclizing agent due to their reactivity towardphosphines.

Examples of solvents which can be used with the divalent mercury reagentinclude the organonitriles, for example, acetonitrile, propionitrile andbutyronitrile, ether solvents, for example, tetrahydrofuran, dioxane,the dimethyl ether of ethylene glycol, diethylether and dibutyl ether;ketones, for example, acetone, methylethyl ketone and diethyl ketone;esters, for example, ethyl acetate, methyl acetate, isoamyl acetate,methyl butyrate and ethyl propionate; and amides such asN,N-dimethylformamide, N,N-dimethylacetate or hexamethylphosphorictriamide (HMPA). Nitrile solvents are preferred when the divalentmercury reagent is used as the cyclization agent.

As mentioned above, in the general formula for the trivalent phosphoruscyclization reagent, R₅ can be C₁ to C₇ alkyl, phenyl, or phenylsubstituted with C₁ to C₄ alkyl or C₁ to C₄ alkoxy. The terms "C₁ to C₇alkyl" is as described above. The term "C₁ to C₄ alkyl" includes methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl andiso-butyl. Representative "C₁ to C₄ alkoxy" groups are methoxy, ethoxy,isopropoxy, tert-butoxy and n-butoxy.

Illustrative of the trivalent phosphorus cyclization reagents which canbe employed are alkyl phosphines such as trimethylphosphine,triethylphosphine, tripropylphosphine, tri(iso-propyl)phosphine,tributylphosphine, tri(tert-butyl)phosphine, tricyclohexylphosphine,tri(4-methylcyclohexyl)phosphine and the like; aryl phosphines such astriphenylphosphine, tri(p-tolyl)phosphine, tri(o-tolyl)phosphine,tri(m-tolyl)phosphine, tri(p-n-propylphenyl)phosphine,tri(p-tert-butylphenyl)phosphine, tri(p-methoxyphenyl)phosphine,tri(p-isopropoxyphenyl)phosphine, o-methoxyphenyldiphenylphosphine,p-methoxyphenyldiphenyl phosphine, and the like; and phosphinescontaining both alkyl and aryl groups, such as dimethylphenylphosphine,diphenylethylphosphine, di(p-methoxyphenyl)methylphosphine,di(p-tolyl)methylphosphine, p-methoxyphenylphenylmethylphosphine,p-tolylphenylmethylphosphine and the like. The preferred phosphine foruse in the process is triphenylphosphine.

As mentioned above, when the process of this application is carried outwith the divalent mercury cyclization reagent, the general formula ofthis reagent is

    Hg(X).sub.2

wherein X is chloro, bromo or trifluoroacetato. The divalent mercurycyclization reagents which can be employed in the present process aredichloromercury(II), dibromomercury(II) orbis(trifluoroacetato)mercury(II). The preferred divalent mercurycyclization reagent is bis(trifluoroacetato)mercury(II).

A preferred group of azetidinone alcohol disulfide compounds describedby this invention which can be converted to the 7α-acylamino-3-methyl1-oxa β-lactam compounds according to the process of this invention arerepresented by the following general formula ##STR13## wherein R₁ is anacyl group of the formula ##STR14## wherein R' is (a) C₁ -C₇ alkyl,cyanomethyl;

(b) C₁ -C₆ alkoxy;

(c) benzyl, phenoxymethyl, p-methoxyphenylmethyl;

(d) 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl,2-thiazolylmethyl, 5-tetrazolylmethyl, 1-tetrazolylmethyl;

(e) 1-protected hydroxybenzyl, 1-protected aminobenzyl, 1-protectedamino(4-protected hydroxybenzyl).

R₂ is tert-butyl, p-methoxybenzyl or diphenylmethyl, and R₃ is anothermolecule of the identically substituted azetidinone alcohol moietybonded to the opposite end of the disulfide group, or is phenyl or amono-substituted phenyl, where the substituents are chloro, methoxy,methyl or acetoxy.

Illustrative of the preferred compounds of the invention, and hence thepreferred group of substituents for the process of this inventioninclude the following symmetrical azetidinone alcohol disulfidecompounds:

4R,4'Rbis[1-(diphenylmethyl-2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

4R,4'R bis[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-thienyl)acetamido)azetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-thiazolyl)acetamidoazetidine]disulfide,

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(1-tetrazolyl)acetamido)azetidine]disulfide,

4R,4'R bis[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-furyl)acetamido)azetidine]disulfide,

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-cyanoacetamidoazetidine]disulfide,

4R,4'R bis[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-benzylcarbonato-2-phenylacetamidoazetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-tert-butoxycarbonylamino-2-phenylacetamido)azetidine]disulfide,

4R,4'R bis[1-diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(tert-butoxycarbonylamino)-2-(4-benzylcarbonatophenyl)acetamido)azetidine]disulfide,

4R,4'R bis[1-diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-benzyloxycarbonyl-2-phenylacetamido)azetidine]disulfide.

Preferred unsymmetrical disulfides of this invention include:

phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

p-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

o-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

p-methoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

p-acetoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

p-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxa-3S-phenoxyacetamidoazetidine]disulfide,

p-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoacetidine]disulfide,

o-methoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

p-acetoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-thienyl)acetamido)azetidine]disulfide,

p-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-thienyl)acetamido)azetidine]disulfide,

m-chlorophenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-thiazolyl)acetamido)azetidine]disulfide,

p-methoxy 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-thiazolyl)acetamido)azetidine]disulfide,

o-methoxy 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(1-tetrazolyl)acetamido)azetidine]disulfide,

p-acetoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-Z-ene-oate)-2-oxo-3S-(2-(1-tetrazolyl)acetamido)azetidine]disulfide,

o-acetoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-furyl)acetamido)azetidine]disulfide,

phenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(2-furyl)acetamido)azetidine]disulfide,

phenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-cyanoacetamidoazetidine]disulfide,

p-chlorophenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-cyanoacetamidoazetidine]disulfide,

o-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-benzylcarbonato-2-phenylacetamidoazetidine]disulfide,

p-methoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-benzylcarbonato-2-phenylacetamidoazetidine]disulfide,

o-methoxybenzyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-tert-butoxycarbonylamino-2-phenylacetamido)azetidine]disulfide,

p-methylphenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-tert-butoxycarbonylamino-2-phenylacetamido)azetidine]disulfide,

m-methylphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(tert-butoxycarbonylamino)-2-(4-benzylcarbonatophenyl)acetamido)azetidine]disulfide,

p-acetoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-tert-butoxycarbonylamino)-2-(4-benzylcarbonatophenyl)acetamido)azetidine]disulfide,

o-acetoxy 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-benzyloxycarbonyl-2-phenylacetamido)azetidine]disulfideand

phenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-benzyloxycarbonyl-2-phenylacetamido)azetidine]disulfide.

A more preferred group of azetidinone alcohol disulfide compounds ofthis invention are again represented by the following general formula##STR15## wherein R₁ is an acyl group of the formula ##STR16## whereinR' is

    R"--(O).sub.m --CH.sub.2 --

wherein R" is phenyl or substituted phenyl wherein the substituents are1 or 2 halogens, protected hydroxy, cyano, trifluoromethyl, C₁ -C₄alkyl, C₁ -C₄ alkoxy, protected carboxy, protected carboxymethyl,protected hydroxymethyl or protected aminomethyl; and m is 0 or 1, R₂ istert-butyl, p-methoxybenzyl or diphenylmethyl and R₃ is another moleculeof the identically substituted azetidinone alcohol moiety bonded to theopposite end of the disulfide group, or is phenyl or a mono-substitutedphenyl, where the substituents are chloro, methoxy, methyl or acetoxy.

Illustrative of the more preferred compounds of this invention, andhence the more preferred group of substrates for the process of thisinvention, are the following symmetrical azetidonone alcohol disulfidecompounds:

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

4R,4'R bis[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(p-methylphenyl)acetamidoazetidine]disulfide,

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(p-methoxyphenyl)acetamidoazetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzylcarbonatophenyl)acetamido)azetidine]disulfide,

4R,4'R bis[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxa-3S-(4-chlorophenylacetamido)azetidine]disulfide,

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-chlorophenylacetamido)azetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(4-trifluoromethylphenylacetamido)azetidine]disulfide,

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzyloxycarbonylphenyl)acetamido)azetidine]disulfide,

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzylcarbonatomethylphenyl)acetamido)azetidine]disulfide,

4R',4'R bis[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzyloxycarbonylmethylphenyl)acetamido)]azetidine]disulfide,

4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-tert-butoxycarbonylaminomethylphenyl)acetamido)azetidine]disulfide,and

4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-cyanophenyl)acetamido)azetidine]disulfide.

The following are illustrative of the more preferred unsymmetricaldisulfides of this invention.

phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

p-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

o-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

p-methoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide,

p-acetoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoacetidine]disulfide,

phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

p-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

p-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

o-methoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

p-acetoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide,

phenyl 4R[1-diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(p-methylphenyl)acetamido)azetidine]disulfide,

p-chlorophenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(p-methylphenyl)acetamido)acetidine]disulfide,

m-chlorophenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(p-methoxyphenyl)acetamido)azetidine]disulfide,

p-methoxyphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(p-methoxyphenyl)acetamido)azetidine]disulfide,

o-methoxyphenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzyloxycarbonylphenyl)acetamido)azetidine]disulfide,

p-methylphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzyloxycarbonylphenyl)acetamido)azetidine]disulfide,

o-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(4-chlorophenylacetamido)azetidine]disulfide,

p-acetoxyphenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(4-chlorophenylacetamido)azetidine]disulfide,

o-acetoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-chlorophenylacetamido)azetidine]disulfide,

phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-chlorophenylacetamido)azetidine]disulfide,

phenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(4-trifluoromethylphenylacetamido)azetidine]disulfide,

p-chlorophenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(4-trifluoromethylphenylacetamido)azetidine]disulfide,

o-chlorophenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzyloxycarbonylphenyl)acetamido)azetidine]disulfide,

p-methoxyphenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-benzyloxycarbonylphenyl)acetamido)azetidine]disulfide,

o-methoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-tert-butoxycarbonylaminomethylphenyl)acetamido)azetidine]disulfide,

p-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-tert-butoxycarbonylaminomethylphenyl)acetamidoazetidine]disulfide,

m-methylphenyl 4R[1-(tert-butyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-cyanophenyl)acetamido)azetidine]disulfideand

p-acetoxyphenyl 4R[1-(p-methoxybenzyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3S-(2-(4-cyanophenyl)acetamido)azetidine]disulfide.

The starting material utilized in the process of this invention issynthesized by first epimerizing the C-6 side chain of a penicillinsulfoxide from the β to the α conformation, followed by therearrangement of the 6α-acylamino-penicillin sulfoxide to thecorresponding 7α-acylamino-3-methyl cephalosporin. The next stepinvolves the 2α-alkoxylation of the above cephalosporin. The final stepin the synthesis of the starting material for this invention involvesthe formation of an azetidinone disulfide aldehyde from the7α-acylamino-2α-alkoxy-3-methyl cephalosporin. Specifically, in thesynthesis of the starting material for the process of this invention,the epimerization at C-6 of the 6β-acylaminopenicillanate-1-sulfoxide,represented by the following scheme: ##STR17## is a process well knownto those skilled in the art. See, for example, Ramsay and Stoodley,Chemical Communications, 1971, 450, Koppel, Tetrahedron Letters, 1973,4233, Stoodley, U.S. Pat. No. 3,853,848, Clair et al, J.C.S. PerkinTransactions I, 937 (1973), and Barton et al, J.C.S. Perkin TransactionsI, 599, 1973. The preferred method of epimerization at the C-6 positioninvolves reacting the naturally occurring 6β-acylamino compound with onemole of trimethylsilyl chloride in methylene chloride at between 0° C.and ambient temperature, cooling the mixture to 0° C., and addingdropwise 2 equivalents of triethylamine. The product can be purified bystandard extraction and recrystallization techniques. The desiredα-isomer can be isolated by dissolving the isomer mixture from thereaction mixture in a minimum quantity of ethyl acetate and adding a fewcrystals of the β-isomer to facilitate crystallization of the β-isomer.The β-isomer crystals are filtered, resulting in a filtrate containingsubstantially pure (approximately 90%) α-isomer of the penicillinate,which α -isomer can be isolated by evaporating the filtrate to dryness.

The preferred procedure of C-6 epimerization is described by Blaszczakin copending application Ser. No. 138,022, entitled "Process forPenicillin Epimerization", filed this even date.

The rearrangement of the 6α-acylaminopenicillinate-1-sulfoxide to thecorresponding 7α-acylamino-3-methyl-3-cephem-4-carboxylate, representedby the following general formula: ##STR18## is analogous to a procedurealso well known to those skilled in the art. Although several variationsof the method are available to effect this rearrangement, the preferredmethod involves reacting the 6α-acylaminopenicillinate-1-sulfoxide withN,O-bis(trimethylsilyl)acetamide (BSA) and α-picoline.HBr in drieddioxane at reflux temperatures. The organic products of the reaction arethen extracted into ethyl acetate, and the extract is treated with neatpyridine. Pure 7α-acylamino-3-methyl-3-cephem-4-carboxylate can beobtained by recrystallization.

The procedure for the above rearrangement step was adapted from onedescribed by Verweij et al., in U.S. Pat. No. 4,003,894.

The next step in the general reaction scheme for preparing the startingmaterial of this invention involves the α-alkoxylation at the C-2position of the cephem moiety. This reaction is represented in thefollowing general formula: ##STR19## As with the above two steps in thesynthesis of this starting material, the 2α-alkoxylation reactioninvolved at this stage of the synthesis is analogous to procedures wellknown to those skilled in the art; see, for example, D. O. Spry,Tetrahedron Letters, 3717 (1972); A. Yoshida, S. Oida, and E. Ohki,Chemical and Pharmaceutical Bulletin of Japan (Tokyo), 23, 2507 and 2518(1975); ibid., 24 362 (1976); ibid. 25, 2082 (1977); C. O. Kim and P. A.McGregor, Tetrahedron Letters, 409 (1978). Although the aforementionedreferences describe various methods of 2α-alkoxylation for 7β-isomers ofcephalosporins, the preferred method for the conversion of7α-acylamino-3-methyl-3-cephem-4-carboxylate to its corresponding2α-alkoxy analog comprises the addition of N-chlorosuccinimide to asolution of the substrate cephem compound dissolved in an appropriatealcohol and methylene chloride at room temperature. The desired2α-alkoxy product can then be isolated by standard crystallization andchromatography techniques.

The final step in the synthesis of the starting materials for thisinvention involves converting the 7α-acylamino-2α-alkoxy-3-methylcephalosporin to an azetidinone aldehyde disulfide.

The disulfide formation step in the above general reaction scheme can beaccomplished in one of two methods, with each method yielding adifferent product. One method of disulfide formation, represented by thefollowing general formula, ##STR20## entails adding the7α-acylamino-2α-alkoxy-3-methyl-3-cephem-4-carboxylate compound to amethylene chloride solution of arylsulfenyl chloride at 0° C. Thedesired aryl 4β[1-(protected carboxy2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3α-acylaminoazetidine]disulfide can be reduced at this point to give theunsymmetrical azetidinone alcohol disulfide compounds of this invention,or may be further purified by conventional chromatographic techniquesbefore submitting these unsymmetrical azetidinone aldehyde disulfides toreduction. This method for disulfide formation is described by Kukoljaand Pfeil in copending application Ser. No. 137,861, entitled"Unsymmetrical Azetidinone Aldehyde Disulfide and Process", filed thiseven date.

The alternate method for disulfide formation represented by thefollowing general formula; ##STR21## involves adding N-chlorosuccinimideto a methylene chloride solution of the appropriate7α-acylamino-2α-alkoxy-3-methyl-3-cephem-4-carboxylate compound at 0° C.This solution is then added to an aqueous suspension of mercurydichloride and cadmium carbonate at room temperature. This method ofdisulfide formation produces a symmetrical disulfide compound that hasidentically substituted azetidinone moieties bonded to either end of thedisulfide linkage, in contrast with the disulfide formation methodemploying an arylsulfenyl chloride, which produces an unsymmetricalazetidinone disulfide compound having an aryl group bonded to one endand an azetidinone moiety bonded to the other end of the disulfidegroup. The 4R,4'R bis[1-(protectedcarboxy[2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo]-3s-acylaminoazetidine]disulfide produced in the former method can be reduced at thispoint to give the symmetrical azetidinone disulfide alcohol compounds ofthis invention, or may be further purified by conventionalchromatographic techniques before submitting these symmetricalazetidinone aldehyde disulfides to reduction. This method of disulfideformation which produde symmetrical azetidinone aldehyde disulfidecompounds is described in Kukolja and Pfeil in copending applicationSer. No. 138,023, entitled "Symmetrical Azetidinone Aldehyde Disulfideand Process", filed this even date.

As indicated in the present application both the symmetrical andunsymmetrical azetidinone aldehyde disulfide compounds are precursors tothe compounds of this invention.

The compounds of this invention are intermediates useful in thepreparation of a particular class of biologically active 1-oxa β-lactamcompounds. These intermediate compounds are cyclized by the process ofthis invention to the desired 7α-acylamino-3-methyl 1-oxa β-lactam. Thisconversion of the azetidinone alcohol disulfide compounds to a 1-oxaβ-lactam and the remaining steps necessary to synthesize the desired7β-acylamino-7α-methoxy-3-methyl 1-oxa β-lactam antibiotic compounds isaccomplished by first 7α-methoxylating the 7α-acylamino 1-oxa β-lactamcompounds obtained from the process of this invention, then by removingthe protecting group on the C-4 carboxylic acid function to give thedesired 7β-acylamino-7α-methoxy 1-oxa β-lactam acid antibioticcompounds.

As mentioned above, the first step in the synthesis of the desiredantibiotic 1-oxa β-lactam compounds involves converting the7α-acylamino-3-methyl 1-oxa β-lactam compound obtained from the processof this invention to the corresponding 7β-acylamino-7α-methoxy-3-methyl1-oxa β-lactam by reacting the 7α-acylamino substrate with lithiummethoxide and tert-butyl hypochlorite. This reaction is representedgenerally by the following formula: ##STR22## The reaction entails theaddition of the 7α-acylamino 1-oxa β-lactam to a suspension of lithiummethoxide in dry tetrahydrofuran in an inert atmosphere followed byaddition of tert-butyl hypochlorite to the solution to initiate themethoxylation. Once the reaction has reached completion, the reaction isquenched with trimethylphosphite and glacial acetic acid. The desiredproduct can be isolated and purified with conventional liquid-liquidextraction techniques.

The conversion of the 7α-acylamino-3-methyl 1-oxa β-lactam to the7β-acylamino-7α-methoxy-3-methyl 1-oxa β-lactam is carried out in amanner analogous to that of G. A. Koppel and R. E. Koehler, Journal ofthe American Chemical Society, 95, 2403 (1973).

The final step in the synthesis of a 1-oxa β-lactam compound from theclaimed symmetrical and unsymmetrical azetidinone alcohol disulfidecompound is to remove the carboxylic acid protecting group from the7β-acylamino-7α-methoxy-3-methyl 1-oxa β-lactam ester, as shown below;##STR23##

The deprotection step is well known to anyone skilled in the art. Forexample, to remove the diphenylmethyl carboxylic acid protecting group,the substrate diphenylmethyl carboxylate is dissolved in anisole andthen treated with trifluoroacetic acid. The resultant7β-acylamino-7α-methoxy-3-methyl 1-oxa β-lactam acids are antibiotics.Further examples of this deprotection step can be found in U.S. Pat. No.4,138,486.

The following Examples (1-3) are provided to further illustrate thisinvention. Preparations 1 through 3 demonstrate a method of synthesizingthe starting materials for the process of the invention, andpreparations 4-8 demonstrate one way of converting the claimed compoundsof this invention into biologically active 1-oxa β-lactam compounds. Itis not intended that this invention be limited in scope by reason of anyof the preparations or examples. In the following preparations andexamples infrared absorption spectra, nuclear magnetic resonancespectra, ultraviolet absorption spectra and optical rotation spectra areabbreviated i.r. n.m.r., u.v. and o.r., respectively. Only the i.r.absorption maxima or peaks attributable to the carbonyl function of theβ-lactam ring are reported. The nuclear magnetic resonance spectra wereobtained on a Varian Associates T-60 Spectrometer usingtetramethylsilane as the reference standard. The chemical shifts areexpressed in δ values in parts per million (ppm) and coupling constants(J) are expressed in Hz.

EXAMPLE 1 4R,4'R Bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide

4R,4'R Bis[1-(diphenylmethyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide (524 mg, 0.51 mmol) was dissolved in a solution of10 ml tetrahydrofuran (THF) and 1 ml of water. The pH of this solutionwas adjusted to 3.5 with a 1 molar THF solution of sodium hydroxide.Sodium cyanoborohydride (63 mg, 1.0 mmol) was added to the solution andthe reaction mixture was stirred at room temperature for 0.5 hour,during which time the pH of the solution was maintained between 3.2 and3.6 with additions of a solution of 3 ml of 1 molar hydrochloric acidand 3 ml of acetic acid in 20 ml of THF. At the end of 0.5 hour, thereaction solution was poured into a solution composed of 75 ml ofsaturated sodium chloride solution and 50 ml of ethyl acetate, and thisresultant mixture was stirred for ten minutes. The layers were thenseparated and the ethyl acetate layer was washed sequentially with water(1×), saturated sodium bicarbonate (1×), water (1×), saturated sodiumchloride (1×), and was then dried over magnesium sulfate, filtered andevaporated to dryness. The resulting colorless foam was the product,4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide (500 mg.): n.m.r. (CDCl₃) δ 2.18 (s, 3, CH₃), 3.48(s, 2, CH₂ Ph), 3.93 and 4.20 (ABq, J=13 Hz, 2, CH₂ OH), 4.87 (dd, J=2and 9 Hz, 1, CH₃ --H) 5.04 (d, J=2 Hz, 1, C₄ --H), 6.86 (s, 1, CHPh₂),and 7.28 (br. s, 16, aromatic H and N-H).

EXAMPLE 2 p-Methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide

p-Methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide (766 mg, 1.2 mmol) was dissolved in 20 ml oftetrahydrofuran (THF) followed by the addition of 2 ml of water. The pHof this solution was adjusted to 3.5 by the addition of a 1 molar THFsolution of sodium hydroxide. Sodium cyanoborohydride (83 mg, 1.32 mmol)was added to the reaction solution, and the solution was stirred atambient temperature for 2 hours, all the while maintaining the pH of thesolution between 3.2 and 3.6 by additions of an acidic solution (3 ml.of 1 molar hydrochloric acid and 3 ml of acetic acid in 20 ml of THF.).At the end of two hours the reaction solution was poured into a solutionconsisting of 75 ml of saturated sodium chloride solution and 50 ml ofethyl acetate, and the resulting suspension was stirred for ten minutes.The ethyl acetate layer from this solution was separated and washed insequence with water (1×), saturated sodium bicarbonate solution (1×),water (1×), saturated sodium chloride solution (1×), dried overmagnesium sulfate, filtered and evaporated to dryness. The solidremaining after evaporation was absorbed onto 3.5 grams of silica, andchromatographed on 10 grams of silica using, in sequence, 100 ml oftoluene, 200 ml of 5% ethyl acetate toluene, 150 ml of 10% ethyl acetatetoluene and 100 ml each of 15%, 20%, 25% and 30% ethyl acetate intoluene. The final fraction collected contained the desired alcoholβ-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide. (116 mg, 15% yield) n.m.r. CDCl₃) δ 2.00 (s, 3,CH₃), 2.30 (s, 3, toluyl --CH₃), 2.88 (br. s, 1, OH), 3.41, 3.90 (ABq,J=13 Hz, 2, CH₂ OH), 3.47 (s, 2, CH₂ Ph), 4.62 (dd, J=3 and 8 Hz, 1,C.sub. 3 -H) 5.17 (d, J=3 Hz, 1, C₄ --H), 6.32 (d, J=8 Hz, 1, N--H),6.97 (s, 1, CHPh₂), 7.25 (m, 19, aromatic protons).

EXAMPLE 3 Phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]-disulfide

Phenyl4R[1-(diphenylmethyl-2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide is dissolved in tetrahydrofuran (THF) then a smallamount of water is added. The pH of this solution is adjusted to 3.5 bythe addition of a 1 molar THF solution of sodium hydroxide. Sodiumcyanoborohydride is added to the reaction solution, and the solution isstirred at ambient temperature for 2 hours, all the while maintainingthe pH of the solution between 3.2 and 3.6 by additions of an acidicsolution (3 ml of 1 molar hydrochloric acid and 3 ml of acetic acid in20 ml of THF). At the end of two hours the reaction solution is pouredinto a solution consisting of saturated sodium chloride solution andethyl acetate, and the resultant suspension is stirred for ten minutes.The ethyl acetate layer from this solution is separated and is washed insequence with water (1×), saturated sodium bicarbonate solution (1×),then dried over magnesium sulfate, filtered, and evaporated to dryness.The solid remaining after evaporation is chromatographed on silica gelusing, in turn, toluene, 5%, 10%, 15%, 20%, 25% and 30% ethyl acetate intoluene.

EXAMPLE 4 7α-Phenylacetamido-3-methyl 1-oxa β-lactam ester

Bis(trifluoroacetato)mercury(II) (1.48 g, 3.4 mmol) and 4R,4'Rbis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide (866 mg, 0.84 mmol) were dissolved under positivepressure of nitrogen in 16 ml. of dried acetonitrile. The reactionmixture was stirred for 0.5 hour at ambient temperature, at the end ofwhich time it was filtered and the filtrate was taken to dryness. Theresulting orange foam was dissolved in ethyl acetate and the ethylacetate solution was washed with water (1×), saturated sodium chloridesolution (1×), and then with a sodium chloride solution until the washwater was neutral. The ethyl acetate layer was filtered through asintered glass funnel, dried over magnesium sulfate, filtered, andevaporated to dryness, yielding a dark orange foam (773 mg). This foamwas recrystallized from an acetone/cyclohexane mixture and subsequentfiltration of this mixture isolated pure crystals of the desiredproduct, diphenylmethyl 7α-phenylacetamido-3-methyl 1-oxa β-lactam ester(65 mg). The filtrate from the above recrystallization was combined withthe filtrate from another experiment done analogous to the aboveprocedure, and this combined filtrate was chromatographed on silica geleluting with 20% ethyl acetate in toluene to give more of the desireddiphenylmethyl 7α-phenylacetamido-3-methyl 1-oxa β-lactam ester (mp190°-191°), i.r. (CHCl₃) 1780 cm⁻¹ ; n.m.r. (d₆ -acetone) δ 1.93 (s, 3,CH₃), 3.6 (s, 2, CH₂ Ph), 4.35 (br, s, 2, C₃ --H), 4.73 (dd, J=1.5 and 9Hz, 1, C₇ --H), 4.99 (d, J=1.5 Hz, 1, C₆ --H), 6.89 (s, 1, CHPh₂), and7.3 (m, 16, aromatic H and N--H); mass spectrum, m/e 406; u.v. λ_(max)263 nm (ε=6,072).

EXAMPLE 5 7α-Phenylacetamido-3-methyl 1-oxa β-lactam ester

Triphenylphosphine (278 mg, 1.06 mmol) and 4R,4'R bis[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide (464 mg, 0.52 mmol) were combined in 10 ml of dry1,2-dichloroethane. The solution was refluxed for seventy minutes, afterwhich time it was evaporated to dryness. The resulting yellow oil waschromatographed on 15 grams of silica gel using 1:1 ethyl acetate/hexaneplus 1/2% acetic acid as the eluant. The pure product, diphenylmethyl7α-phenylacetamido-3-methyl 1-oxa β-lactam (67 mg), possessed the samephysical properties as the product compound in Example 4.

EXAMPLE 6 7α-Phenylacetamido-3-methyl 1-oxa β-lactam ester

The following reaction was carried out in an inert atmosphere (N₂) untilafter evaporation of the reaction solution. p-Methylphenyl4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide (0.1 g, 0.16 mmol) was dissolved in 5 ml of driedacetonitrile. Bis(trifluoroacetato)mercury(II) (136 mg, 0.32 mmol) wasadded to the reaction solution and the solution was stirred at ambienttemperature for 0.5 hour, during which time the color of the reactionsolution changed from yellow to orange. The solution was evaporated todryness, and the resulting solid was dissolved in ethyl acetate. Thisethyl acetate solution was washed with water (1×), sodium bicarbonatesolution (2×), sodium chloride solution (1×), dried over magnesiumsulfate, filtered then evaporated to dryness. The resultant solid waschromatographed on a preparative-scale thin layer chromatography plateusing a 1:1 solution of ethyl acetate/hexane as the eluant, yielding thepure 7α-phenylacetamido-3-methyl 1-oxa β-lactam ester compound (37 mg,49% yield) which possessed the same physical properties as the productcompound in Example 4.

EXAMPLE 7 7α-Phenylacetamido-3-methyl 1-oxa β-lactam ester

Triphenylphosphine and p-methylphenyl 4R-[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide are combined in dry 1,2-dichloroethane. The solutionis refluxed for seventy minutes, after which time it is evaporated todryness. The resultant crude 7α-phenylacetamido-3-methyl 1-oxa β-lactamdiphenylmethyl ester is chromatographed on silica gel using an equalvolume mixture of ethyl acetate and hexane plus 1/2% acetic acid as theeluant.

EXAMPLE 8 7α-Phenylacetamido-3-methyl 1-oxa β-lactam diphenylmethylester.

The following reaction is carried out in an inert atmosphere until afterevaporation of the reaction solution. Phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide is dissolved in dried acetonitrile.Bis(trifluoroacetato)mercury(II) is added to the reaction solution andthe solution is stirred at ambient temperature for 0.5 hour. Thesolution is evaporated to dryness, and the resultant solid is dissolvedin ethyl acetate. This ethyl acetate solution is washed with water (1×),sodium bicarbonate solution (2×), sodium chloride solution (1×), isdried over magnesium sulfate, is filtered then is evaporated to dryness.The resultant solid is chromatographed on a preparatory-scale thin layerchromatography plate using a 1:1 solution of ethyl acetate/hexane as theeluant.

EXAMPLE 9 7α-Phenylacetamido-3-methyl 1-oxa β-lactam diphenylmethylester.

Triphenylphosphine and phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-ol-Z-but-2-ene-oate)-2-oxo-3s-phenylacetamidoazetidine]disulfide is combined in dry 1,2-dichloroethane. The solutionis refluxed for seventy minutes, after which time it is evaporated todryness. The resultant crude 7α-phenylacetamido-3-methyl 1-oxa β-lactamdiphenylmethyl ester is chromatographed on silica gel using an equalvolume mixture of ethyl acetate and hexane plus 1/2% acetic acid as theeluant.

PREPARATION 1 Benzyl 6α-phenylacetamidopenicillanate-1-sulfoxide

Benzyl 6β-phenylacetamidopenicillanate-1-sulfoxide (8.80 g, 20 mmol) wasdissolved in 17 ml of methylene chloride under a positive nitrogenpressure, and the resultant solution was cooled to 2° C. in an ice/waterbath. Triethylamine (6.1 ml, 43.8 mmol) was added to the cooledsolution, which resulted in the precipitation of the penicillinate.Thirteen more ml of methylene chloride were added to the solution todissolve the penicillinate, followed by the addition ofchlorotrimethylsilane (2.8 ml, 22 mmol). The reaction solution wasstirred for 1 hour at 0° C., allowed to warm to ambient temperature andstirred for 1.5 hours longer, at the end of which time morechlorotrimethylsilane (1 ml, 7.86 mmol) was added and the stirring wascontinued for an additional 45 minutes. After cooling the reactionmixture to 4° C., acetic acid (3 ml, 52 mmol) was added dropwise,followed by addition of methylene chloride (20 ml). The reactionsolution was then washed with 1 molar hydrochloric acid (3×) and with asaturated sodium bicarbonate solution (2×). The layers were separated,and the water layer was extracted with methylene chloride. The methylenechloride layers were combined, washed with a saturated sodium chloridesolution (1×) then dried over magnesium sulfate, filtered and evaporatedto dryness. The resultant off-white foam (8.3 g) was recrystallized froma 1:1 mixture of ethyl acetate/cyclohexane. Five grams of thecrystallized product was dissolved in 13 ml of ethyl acetate, and seededwith benzyl 6β-phenylacetamidopenicillanate-1-sulfoxide crystals, toyield white crystals of the 6β-isomer of the penicillanate (760 mg). Thecrystals of the 6β-isomer of the penicillanate of benzyl6-phenylacetamidopenicillanate-1-sulfoxide were filtered off and thefiltrate yielded predominately pure (approximately 90%) 6α-isomer ofbenzyl 6-phenylacetamidopenicillanate-1-sulfoxide. (4.06 g, 46% yield).n.m.r. (d₅ -pyridine) δ 1.13, 1.62 (s, 6, C(CH₃)₂, 3.78 (s, 2, COCH₂Ph), 4.92 (s, 1, C₃ --H), 5.22 (br. s, 2, CO₂ CH₂ Ph), 5.52 (d, J=2 Hz,1, C₅ --H), 5.88 (dd, J=2 and 8 Hz, 1, C₆ --H), 7.33 (m, 10, aromatic),10.13 (d, J=8 Hz, 1, NH).

PREPARATION 2 Benzyl 7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate

To a solution of benzyl 6α-phenylacetamidopenicillanate-1-sulfoxide(31.4 g, 71.6 mmole) in dried dioxane (500 ml) was addedN,O-bis[trimethylsilyl] acetamide (BSA) (39 ml, 158 mmole) and 58 ml ofan α-picoline.HBr solution (1.23 M in CH₂ Cl₂, 71.6 mmol). This reactionmixture was refluxed for 5 hours, during which time the color of thereaction solution color changed from yellow to brown. The reactionsolution was cooled to ambient temperature and poured into a stirringmixture of 1:1 ethyl acetate/ice water. The layers were separated andthe ethyl acetate layer was washed sequentially with saturated sodiumchloride solution (1×), 1 molar hydrochloric acid (4×), saturated sodiumbicarbonate solution (1×), and again with saturated sodium chloridesolution (2×). The ethyl acetate layer was then dried over magnesiumsulfate, filtered, evaporated to dryness, and treated with neat pyridine(10 ml, 0.12 mole) for 1 hour. The pyridine solution was taken up inmethylene chloride and washed first with 1 molar hydrochloric acidseveral times, then with brine solution (1×). The extract was dried overmagnesium sulfate, filtered and evaporated to dryness. The resultantcrude product was recrystallized by dissolution in a 7:1 ethylacetate:cyclohexane solution and addition of a few seed crystals of thetitle product. Two crops of crystals were collected and gave a combinedyield of 8.70 grams (29% yield) of substantially pure7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate (m.p. 169°-170° C.);i.r. (CHCl₃) 1773 cm⁻¹ ; n.m.r. (CDCl₃) δ 2.00 (s, 3, CH₃), 3.10. 3.37(ABq, J=15 Hz, 2, C₂ --H), 3.53 (s, 2, COCH₂ Ph), 4.55 (d, J=2 Hz, 1, C₆--H), 4.85 (dd, J=2 and 8 Hz, 1, C₇ --H), 5.10 (s, 2, CO₂ CH₂ Ph), 6.98(d, J=8 Hz, 1, NH), 7.27 (s, 5, aromatic protons) and 7.35 (s, 5,aromatic protons); u.v. (CHCl₃) λ_(max) 264 nm (ε=8,210), o.r. [α]_(D)²⁵° +46.9° ; mass spectrum, m/e 4.22.

Analysis: Calculated for C₂₃ H₂₂ N₂ O₃ S: C, 65.38; H, 5.25; N, 6.63; O,15.15; S, 7.59. Found: C, 65.25; H, 5.09; N, 6.63; O, 14.88; S, 7.44.

PREPARATION 3 Diphenylmethyl7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate

To a solution of diphenylmethyl7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole)in 40 ml of methanol and 60 ml of methylene chloride, was addedN-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for90 minutes at room temperature. The reaction solution was then washedwith brine (2X) and dried over magnesium sulfate, filtered, and thesolvent was evaporated under reduced pressure. The resultant yellow foam(2.84 g) was chromatographed over 100 grams of silica gel employing10-15% of ethyl acetate in toluene as the eluting solvent. The firstfraction to elute from the column was the desired 2α-methoxy cephemcompound which was subsequently recrystallized from a mixture of ethylacetate and cyclohexane to give pure diphenylmethyl7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg,21% yield) (mp 144°-145° C.) i.r. (CHCl₃) 1780, 1725 and 1680 cm⁻¹ ;n.m.r. (CDCl₃) δ1.95 (s, 3, CH₃) 3.35 (s, 3, OCH₃), 3.45 (s, 2, CH₂ Ph),4.60 (s, 1, C₂ --H), 4.70 (d, J=2 and 8 Hz, 1, C₇ --H), 4.85 (d, J=2 Hz,1, C₆ --H), 6.95 (s, 1, CH₂ Ph), 7.3 (m, 16, aromatic H and N--H); u.v.(CHCl₃) λ_(max) 264 nm (ε=9726).

Analysis: Calculated for C₃₀ H₂₈ N₂ O₅ S: C, 68.16; H, 5.34; N, 5.30; S,6.07. Found: C, 68.36; H, 5.33; N, 5.29; S, 5.90.

PREPARATION 4 4R,4'R bis[1-(benzyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]-disulfide

To a solution of diphenylmethyl7α-(2-phenylacetamido)-2α-methoxy-3-methyl-3-cephem-4-carboxylate (1.6g, 3.5 mmol) in 50 ml of methylene chloride at 0° C. was addedN-chlorosuccinimide (0.49 g, 3.64 mmol). The solution was stirred for 15minutes, then was added to a rapidly stirring suspension of mercurydichloride (2.9 g, 10.6 mmol) and cadmium carbonate (3.78 g, 22 mmol) in50 ml of water. The mixture was stirred at ambient temperature for 30minutes, and filtered through pre-washed Celite. The methylene chloridewas then separated and evaporated to dryness. The product was taken upin ethyl acetate and the ethyl acetate solution was washed with water(5×) then with saturated sodium chloride solution (1×) and subsequentlydried over magnesium sulfate and filtered. Evaporation to dryness gavecrude product (1.5 g, 99% yield) of which 800 mg was chromatographed on15 grams of silica gel using 1:1 ethyl acetate:hexane as the eluant. Theproduct, 4R,4'R bis[1-(benzyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide was isolated as a yellow foam (247 mg, 62% yield)i.r. (CHCl₃) 1785 cm⁻¹ ; n.m.r. (CDCl₃) δ 2.00 (s, 3, CH₃), 3.52 (s, 2,CH₂ Ph), 4.90 (dd, J=2 and 8 Hz, 1, C₃ --H), 5.2 (br. s, 2, CO₂ CH₂ Ph)5.33 (d, J=2 Hz, 1, C₄ --H), 7.25 (s, 10, aromatic H), 7.60 (d, J=8 Hz,1, N--H), 9.8 (s, 1, CHO); u.v. λ_(max) (CHCl₃)=291 nm, (ε=14,567).

Analysis: Calculated for C₅₈ H₅₀ N₄ O₁₀ S₂ : C, 63.14; H, 4.84; N, 6.40;O, 18.28; S, 7.33; Found: C, 63.21; H, 4.97; N, 6.16; O, 18.40; S, 7.08.

PREPARATION 5 4R,4'R bis[1-(tert-butyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-(2-isobutoxycarbonylamino-2-phenylacetamidoazetidene]disulfide

To a solution of tert-butyl7α-(2-isobutoxycarbonylamino-2-phenylacetamido)-2α-methoxy-3-methyl-3-cephem-4-carboxylatein methylene chloride cooled to 0° C. is added N-chlorosuccinimide. Thissolution is stirred for 15 minutes, and then is added to a rapidlystirring suspension of mercury dichloride and cadmium carbonate inwater. The resultant reaction mixture is stirred at ambient temperaturefor 30 minutes and is filtered through pre-washed Celite. The methylenechloride is then separated and evaporated to dryness. The product istaken up in ethyl acetate and the ethyl acetate solution is washed withwater (5×) then with saturated sodium chloride solution (1×) and issubsequently dried over magnesium sulfate. Filtration and evaporation todryness gives crude product which is chromatographed on silica gel using1:1 ethyl acetate:hexane as the eluant.

PREPARATION 6 4R,4'R bis [1-(p-methoxybenzyl2-N-3methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenoxyacetamidoazetidine]disulfide

To a solution of 4-methoxybenzyl7-(2-phenoxyacetamido)-2α-methoxy-3-methyl-3-cephem-4-carboxylate inmethylene chloride at 0° is added N-chlorosuccinimide. The solution isstirred for 15 minutes, then is added to a rapidly stirring suspensionof mercury dichloride and cadmium carbonate in water. The mixture isstirred at ambient temperature for 30 minutes, and is filtered throughpre-washed Celite. The methylene chloride is the separated andevaporated to dryness. The product is taken up in ethyl acetate and theethyl acetate solution is washed with water (5×) then with saturatedsodium chloride solution (1×) and is subsequently dried over magnesiumsulfate. Filtration and evaporation to dryness gives crude product whichis chromatographed on silica gel using 1:1 ethyl acetate:hexane as theeluant.

PREPARATION 7 p-Methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide

Sodium bicarbonate (95 mg, 1.1 mmol) was dissolved in 25 ml methylenechloride then cooled to -20° C. A one molar methylene chloride solutionof chlorine (1.1 ml, 1.1 mmol) was pipetted into the cooled sodiumbicarbonate solution followed by the dropwise addition of a methylenechloride solution of p-methylphenylmercaptan (140 mg, 1.1 mmol wasdissolved in 5 ml of methylene chloride). The resultant solution wasstirred at -20° C. for 0.5 hour, at the end of which time diphenylmethyl7α-benzamido-2α-methoxy-3-metyl-3-cephem-4-carboxylate (528 mg, 1 mmol)was added and the resultant solution was stirred at 0° C. for 0.5 hour,then evaporated to dryness. The resultant residue was dissolved in ethylacetate, and this solution was washed with sodium bicarbonate solution(2×), water (1×), sodium chloride solution (1×), dried over magnesiumsulfate, filtered and evaporated to dryness. The yellow foam remainingafter evaporation was absorbed on to 2.5 grams of silica andchromatographed over 7 g. of silica employing first 100 ml of toluene,then 100 ml 5% ethyl acetate/toluene and finally 150 ml of 10% ethylacetate/toluene as the eluant. The last fraction collected yielded thedesired aldehyde disulfide, p-methylphenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide (374 mg, 59% yield); i.r. (CHCl₃) 1780 cm⁻¹ ; n.m.r.(CDCl₃) δ 1.73 (s, 3, CH₃), 2.20 (s, 3, toluyl CH₃), 3.48 (s, 2, CH₂Ph), 4.68 (dd, J=3 and 8 Hz, 1, C₃ --H), 5.35 (d, J=3 Hz, 1, C₂ --H),6.38 (d, J=8 Hz, 1, NH), 7.00 (s, 1, CHPh₂), 6.8-7.6 (m, 19, aromaticprotons), 9.32 (s, 1, aldehydic proton); u.v. (CHCl₃) λ_(max) =294 nm(ε=5,500).

PREPARATION 8 Phenyl 4R[1-(diphenylmethyl2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]-disulfide

Phenylmercaptan (0.105 ml, 1 mmol) was added a solution of sodiumbicarbonate (84 mg, 1 mmol) suspended in methylene chloride (25 ml) at0° C., followed by addition of 1 molar chlorine solution (1 ml, 1 mmol,methylene chlorine solution). The reaction mixture was stirred for 2hours at the end of which time diphenylmethyl7α-phenylacetamido-2α-methoxy-3-methyl-3-methyl-3-cephem-4-carboxylate(528 mg, 1 mmol), dissolved in 10 ml of methylene chloride, was added tothe reaction mixture. The mixture was stirred for 45 minutes at 0° C.then for an additional 15 minutes after the ice bath was removed. Thesolution was evaporated to dryness, dissolved in ethyl acetate, added toan aqueous sodium bicarbonate solution and stirred for 15 minutes atroom temperature. After separation and removal of the aqueous layer, theethyl acetate layer was washed successively with 1 molar hydrochloricacid solution (1×), water (1×) and sodium chloride solution (1×). Thesolution was then evaporated to dryness, adsorbed onto 2 grams of silicagel and chromatographed over6 grams of silica gel, eluting successivelywith 100 ml of toluene, 100 ml of 5% ethyl acetate/toluene, 200 ml 8%ethyl acetate/toluene, and finally with 150 ml 12% ethylacetate/toluene. The second fraction collected yielded the desiredaldehyde, phenyl4R[1-(diphenylmethyl-2-N-3-methyl-4-al-Z-but-2-ene-oate)-2-oxo-3S-phenylacetamidoazetidine]disulfide (163 mg., 35% yield). i.r. (CHCl₃) 1785 cm⁻¹ ;n.m.r. (CDCl₃) δ 1.73 (s, 3, CH₃), 3.52 (s, 2, CH₂ Ph), 4.65 (dd, J=3and 7 Hz, 1, C₃ --H), 5.37 (d, J=3 Hz, 1, C₂ --H), 6.17 (d, J=8 Hz, 1,NH), 7.02 (s, 1, CHPh₂), 7.20-7.50 (m, 20, aromatic protons), 9.35 (s,1, aldehydic proton); u.v. (CH₃ CN) λ_(max) =293 nm (ε=3,900).

PREPARATION 9 7β-Phenylacetamido-7α-methoxy-3-methyl 1-oxa β-lactamdiphenylmethyl ester

7α-Phenylacetamido-3-methyl 1-oxa β-lactam diphenylmethyl ester (121 mg,0.25 mmol) was added to a suspension of lithium methoxide in 5 ml of dryTHF (made by adding 1 ml dry methanol to 5.8 mg, 0.83 mmol of lithium inTHF) under positive N₂ pressure at -70° C. tert-Butyl hypochlorite(0.0356 ml, 0.315 mmol) was added to this solution which was thenstirred for 30 minutes at -70° C., at the end of which timetrimethylphosphite (0.0075 ml) and then glacial acetic acid (0.0625 ml)were added to the solution to quench the reaction. The reaction mixturewas allowed to warm to ambient temperature, was evaporated to dryness,and the residue was dissolved in ethyl acetate/water solution and washedsequentially with 1 molar hydrochloric acid solution (1×), brine (1×),5% sodium bicarbonate solution (1×), water (1×), and brine (1×). Thewashed solution was dried over magnesium sulfate, filtered and thenevaporated to dryness to give a white foam of the product7β-phenylacetamido-7α-methoxy-3-methyl 1-oxa β-lactam diphenylmethylester (123 mg). Recrystallization from acetone gave white crystals, (mp.187°-187.5° C.) (88% yield): i.r. (CHCl₃) 1780 cm⁻¹ ; n.m.r. (d₆-acetone) δ 1.99 (s, 3, CH₃), 3.46 (s, 3, OCH₃), 3.68 (s, 2, CH₂ Ph),4.34 (br. s, 2, C₂ --H), 5.05 (s, 1, C₆ --H), 6.91 (s, 1, CHPh₂), and7.3 (m, 16, aromatic H and N--H); mass spectrum, m/e 512.

PREPARATION 10 7β-Phenylacetamido-7α-methoxy-3-methyl-1-oxa β-lactamacid.

7β-Phenylacetamido-7α-methoxy-3-methyl 1-oxa β-lactam diphenylmethylester (50 mg. 0.01 mmol) was dissolved in 0.1 ml of anisole, cooled to0° C., and trifluoroacetic acid (0.4 ml) was slowly added to thereaction mixture. The reaction mixture was stirred for 10 minutes at 0°C., was diluted with ethyl acetate, was evaporated at ambienttemperature, and the resulting colorless oil was taken up in 20 ml ofethyl acetate at 0° C. Cold water (10 ml) was added to the ethyl acetatesolution, the resulting slurry was adjusted to pH 8 with 0.04 molarsodium hydroxide solution and the layers were then separated. Ten ml ofethyl acetate at 0° C. was added to the water layer, and the pH of theresulting slurry was adjusted to pH 3.0 (at 0° C.) with 0.04 molarhydrochloric acid. The layers were separated, and the ethyl acetatelayer was washed with saturated sodium chloride solution (1×), driedover magnesium sulfate, filtered and evaporated to dryness. The crudeproduct was recrystallized from acetone to give pure7β-phenylacetamido-7α-methoxy-3-methyl 1-oxa β-lactam acid (20 mg, 59%yield) (mp 169°-170° C.): i.r. (KBr) 1782 cm⁻¹ ; n.m.r. (d₆ -acetone) δ2.00 (s, 3, CH₃), 3.43 (s, 3, OCH₃), 3.53 (s, 2, CH₂ Ph), 4.39 (br. s,2, C₂ --H), 5.07 (s, 1, C₆ --H), 5.70 (br. s, 1, COOH), 7.33 (s, 5,aromatic H), and 7.95 (s, 1, N--H).

We claim:
 1. A compound of the formula; ##STR24## wherein R₁ is an acylgroup of the formula ##STR25## wherein R' is (a) C₁ -C₇ alkyl,cyanomethyl, C₁ -C₆ haloalkyl,4-protected amino-4-protectedcarboxybutyl; or(b) C₁ -C₆ alkoxy, phenoxy, benzyloxy or4-methoxybenzyloxy; or (c) the group --R" wherein R" is phenyl orsubstituted phenyl wherein the substituents are 1 or 2 halogens,protected hydroxy, cyano, trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,protected carboxy, protected carboxymethyl, protected hydroxmethyl orprotected aminomethyl; or (d) an arylalkyl group of the formula

    R"--(O).sub.m --CH.sub.2 --

wherein R" is as defined above, and m is 0 or 1; or (e) a substitutedarylalkyl group of the formula ##STR26## wherein R'" is R" as definedabove, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl; W is protected hydroxy,protected carboxy, protected amino, or (f) a heteroarylmethyl groups ofthe formula

    R""--CH.sub.2 --

wherein R'''' is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl,5-tetrazolyl, 1-tetrazolyl; R₂ is a carboxy protecting group and R₃ isanother identically substituted azetidinone alcohol moiety bonded to theopposite end of the disulfide group or is phenyl or a monosubstitutedphenyl group, where the substituents are chloro, methoxy, methyl oracetoxy.
 2. The compound of claim 1 wherein R₂ is diphenylmethyl,tert-butyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, trityl,4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl.
 3. Thecompound of claim 1 wherein R₃ is phenyl or p-methylphenyl.
 4. Thecompound of claim 1 wherein R₃ is another molecule of the identicallysubstituted azetidinone alcohol moiety bonded to the opposite end of thedisulfide group.
 5. The compound of claim 4 wherein R₁ is an acyl groupof the formula ##STR27## wherein R' is (a) C₁ -C₇ alkyl, cyanomethyl;(b)C₁ -C₆ alkoxy; (c) benzyl, 1-phenoxymethyl, 1-p-methoxyphenylmethyl; (d)2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl,2-thiazolylmethyl, 5-tertazolylmethyl, 1-tetrazolylmethyl; (e)1-protected hydroxy-1-phenylmethyl, 1-protected amino-1-phenylmethyl,1-protected amino-1-(4-protected hydroxyphenyl)methyl.
 6. The compoundof claim 5 wherein R₂ is diphenylmethyl, tert-butyl, p-methoxybenzyl,2,4,6-trimethylbenzyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl and4,4',4"-trimethoxytrityl.
 7. The compound of claim 6 wherein R₂ isdiphenylmethyl.
 8. The compound of claim 1 wherein R₃ is phenyl or amono-substituted phenyl, where the substituents are chloro, methoxy,methyl or acetoxy.
 9. The compound of claim 8 wherein R₂ equals an acylgroup of the formula ##STR28## wherein R' is (a) C₁ -C₇ alkyl,cyanomethyl;(b) C₁ -C₆ alkoxy; (c) benzyl, 1-phenoxymethyl,1-p-methoxyphenylmethyl; (d) 2-thienylmethyl, 3-thienylmethyl2-furylmethyl, 3-furylmethyl, 2-thiazolylmethyl, 5-tetrazolylmethyl; (e)1-protected hydroxy-1-phenylmethyl, 1-protected amino-1-phenylmethyl,1-protected amino-1-(4-protected hydroxyphenyl)methyl.
 10. The compoundof claim 9 wherein R₃ is phenyl or p-methylphenyl.
 11. The compound ofclaim 10 wherein R₂ is diphenylmethyl, tert-butyl, p-methoxybenzyl,2,4,6-trimethylbenzyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl and4,4',4"-trimethoxytrityl.
 12. The compound of claim 11 wherein R₂ isdiphenylmethyl.
 13. The compound of claim 1 wherein R₃ is anothermolecule of the identically substituted azetidinone alcohol moietybonded to the opposite end of the disulfide group.
 14. The compound ofclaim 13 wherein R₁ is an arylalkyl group of the formula ##STR29##wherein R" is phenyl or substituted phenyl wherein the substituents are1 or 2 halogens, protected hydroxy, cyano, trifluoromethyl, C₁ -C₄alkyl, C₁ -C₄ alkoxy, protected carboxy, protected carboxymethyl,protected hydroxymethyl or protected aminomethyl; and m is 0 or
 1. 15.The compound of claim 14 wherein R₂ is diphenylmethyl, tert-butyl,p-methoxybenzyl, 2,4,6-trimethylbenzyl, trityl, 4-methoxytrityl,4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl.
 16. The compound ofclaim 15 wherein R₁ is benzoyl.
 17. The compound of claim 16 wherein R₂is diphenylmethyl.
 18. The compound of claim 1 wherein R₃ is phenyl ormono-substituted phenyl where the substituents are chloro, methoxy,methyl or acetoxy.
 19. The compound of claim 18 wherein R₁ is anarylalkyl group of the formula ##STR30## wherein R" is phenyl orsubstituted phenyl wherein the substituents are 1 or 2 halogens,protected hydroxy, cyano, trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,protected carboxy, protected carboxymethyl, protected hydroxymethyl orprotected aminomethyl; and m is 0 or
 1. 20. The compound of claim 19wherein R₃ is phenyl or p-methylphenyl.
 21. The compound of claim 20wherein R₂ is diphenylmethyl, tert-butyl, p-methoxybenzyl,2,4,6-trimethylbenzyl, trityl, 4-methoxytrityl, 4,4'-di-methoxytrityl,4,4',4"-trimethoxytrityl.
 22. The compound of claim 21 wherein R₁ isbenzoyl.
 23. The compound of claim 22 wherein R₂ is diphenylmethyl. 24.The compound of claim 23 wherein R₃ is phenyl.
 25. The compound of claim23 wherein R₂ is p-methylphenyl.